POST PCI BLEED,HOW TO MANAGE?

DR.MANISH VINAYAK

Percutaneous coronary interventions (PCIs) are central to the treatment of coronary artery disease, but their invasive nature in conjunction with the use of anticoagulants makes bleeding complications an important peri-procedural risk.

Any amount of bleeding, including minor bleeding, that results from PCI is associated with worse ischemic outcomes such as myocardial infarction, stent thrombosis and death.

It is now widely recognized that there is a stepwise increase in both short- and intermediate-term mortality as bleeding severity worsens.

Impact of Therapies on Outcomes

BleedingIschemic events:

MI/CKMB↑Stent Thrombosis

Bleeding and MortalityMajor Bleeding

TransfusionHypotension

Ischemia Stent Thrombosis Inflammation

Mortality

Cessation of ASA/Clop

Bhatt DL. In Braunwald EB, Harrison’s Online. 2005.

Bleeding: Clinical Consequences

Not only does bleeding result in an immediate threat, but it is also associated with increased coronary artery disease mortality and reinfarction, both in the short and long term.

Major bleeding is associated with a 60% increased risk of in-hospital death, and a five-fold increase in one-year mortality and reinfarction.

DEFINITION(S) One of the obstacles to fully understand the impact of

bleeding after PCI is the inconsistency in definitions used to define a bleeding event.

Steinhubl et al. analyzed bleeding data from 13 large trials evaluating antithrombotic drugs in ACS patients. They concluded that variations in definitions used to define major bleeding have led to differences in reported rates.

Bleeding Definitions : Need for Standardized Definitions

Steinhubl SR . Am Heart J 2007;154:3-11.

Examples of frequently used classifications of bleeding events

Eur Heart J. 2011 Aug;32(15):1854-64.

Two commonly used definitions in the past were the Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding definitions.

Definitions of Major/Severe Bleeding in Randomized Controlled Clinical Trials

PLATO

ACUITYHORIZON

S

STEEPLE

CUREOASIS-5ESSENC

E

REPLACE-2

TIMI phase

II

TIMI phase I

GUSTO

Type of bleeding

+ + + + + + + + + Intracranial/intracerebral

+ + + + + + - - - Intraocular

- + + + + + - - - Retroperitoneal

+ - + + - - - - +Bleeding causing hemodynamic compromise

+ - - - - - + + - Cardiac tamponade

+ + + + - - - - - Bleeding requiring surgical intervention

- + - - - - - - - Hematoma >5cm at the puncture site

≥4 ≥1 ≥1 ≥2 ≥2 ≥2 ≥1 ≥1 ≥1 Transfusion, units

≥5.0

≥3.0 ≥3.0 - ≥3.0 ≥3.0 ≥3.0 ≥5.0* - Decrease in Hgb with overt bleeding, g/dL

- ≥4.0 -≥5.0

- ≥4.0 - - -Decrease in Hgb without overt bleeding, g/dL

*Or decrease in Hct ≥15%

TIMI

Major: Intracranial or

≥ 5 g/dl decrease in the hemoglobin concentration or

≥ 15% decrease in HCT.

Minor: Observed blood loss with

≥ 3 g/dl decrease in the Hgb concentration or

≥ 10% decrease in HCT.

Nonobserved blood loss with

≥4 g/dl dec in Hgb or

≥12% dec in HCT

Minimal: All other bleeding

GUSTO

Severe or life-threatening: Intracranial or bleeding that causes hemodynamic

compromise and requires intervention.

Moderate: Bleeding that requires blood transfusion but does not

result in hemodynamic compromise.

Mild: Bleeding that does not meet criteria for either severe or

moderate bleeding.

ACUITY

Major Intracranial or intraocular bleeding Access site bleeding requiring intervention Hematoma ≥ 5 cm in diameter Drop in Hgb ≥ 4 g/dl without overt source of bleeding or

≥ 3 g/dl with an overt source Bleeding requiring reoperation or transfusion

Minor All other bleeding

REPLACE-2

MAJOR BLEEDING: intracranial, intraocular or retroperitoneal

hemorrhage, clinically overt blood loss resulting in a decrease in hemoglobin >3g/dl,

Any decrease in hemoglobin > 4 g/dl, transfusion of ≥ 2 units PRBCs or whole

blood

BARC (Bleeding Academic Research Consortium)

Eur Heart J. 2011 Aug;32(15):1854-64.

How frequent is bleeding in Patients undergoing PCI?

Major Bleeding Rates in Recent Randomized Clinical Trials

Depend on :

- bleeding definitions

- use of combinations of antithrombotic drugs 6

5

4

3

2

1

0

- clinical setting (elective or urgent)

With GPIIb/IIIa

Without GPIIb/IIIa

On average, 2% of PCI procedures are complicated by a bleeding event.

Bleeding Rates Vary According to the Clinical Setting for PCI

HORIZON Bival vs UFH/GPI

ACUITY Bival vs UFH/GPI

STEEPLE Enox vs UFH

Montalescot et al. NEJM 2006. Stone et al. NEJM 2006 & 2008.

Bleeding Rates Vary According to the Antiplatelet Therapy

CURRENT-TRITON- PLATO

TIMI18

Wiviott SD et al N Engl J Med 2007;35

OASIS7

double-dose clopidogrel

Wallentin L et al N Engl J Med 2009;361:1045-57. Mehta SR et al. Lancet 2010;376:1233-43.

Bleeding Rates Vary According to the Combination of Antithrombotic Drugs

REPLACE-2 Trial (N=6,010; elective or urgent PCI)

4,0% 4,0%

4.0% 4.1%3,5% 3,5%

p=0.0251 p=0.00213,0% 3,0%

2,5% 2,5%

2.5%2,0% 2,0% 2.2%

1,5% 1,5%

1,0% 1,0%

0,5% 0,5%

0,0% 0,0%

Bivalirudin Abciximab Bivalirudin Eptifibatide+ UFH + UFH

Voeltz MD, et al. Circulation 2005;112(17):II-737.

Incidence of Bleeding is decreasing over the years

Data on 10,974 patients who underwent PCI.Kinnaird TD et al, Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003;92:930-5

Bleeding occurred in 7328 [2.4%] of patients

38

12.818.7

5.4

25 Entry Site

Retroperitoneal

GIT

Genitourinary

Other

Circ Cardiovasc Intervent. 2009;2:222-229

PREDICTORS OF BLEEDING

Predictors of Major Bleeding in PCI REPLACE-2 Trial (N=6,010):

Baseline risk factors

Age ≥ 75

Gender (Female)

Creatinine Clearance (per g/dl increase)

Anemia

Prior Angina

Peri-procedural risk factors

Treatment Group (Heparin + GPI vs. bivalirudin)

Provisional GPI received

Procedure Duration >1h

Time to Sheath Removal >6h

Intensive Care Unit stay (days)

Intra-aortic Balloon Pump

1 2 3 4

Feit F, Voeltz MD, Attubato MA, et al. Am J Cardiol 2007

The REPLACE-2 Trial (N=6,010):

Bleeding and Chronic Kidney Disease in PCI

≥ 60 ml/min N=4824

< 60 ml/min N=886

p value

30-d Death 5 (0.1%) 14 (1.6%) < 0.001

30-d Myocardial infarction 305 (6.3%) 75 (8.5%) 0.018

30-D urgent revascularization 61 (1.3%) 10 (1.1%) 0.738

Triple ischemic endpoint 338 (7.0%) 84 (9.5%) 0.010

In-hospital protocol major bleeding 123 (2.5%) 54 (6.1%) < 0.001

TIMI major + minor bleeding 114 (2.4%) 46 (5.2%) < 0.001

Creatinine Clearance

Chew DP, Lincoff AM, Gurm H, et al. Am J Cardiol 2005;95:581–585.

The REPLACE-2 Trial (N=6,010):

Major Bleeding and Anemia in PCI

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

4.5%

5.0%

Non-Anemic Anemic

Overall REPLACE-2 Major bleeding = 3.2%

Major Bleeding 2.8%

4.9%

P=0.0001

Protocol definition: >3g/dL drop in HgB,

intracranial, retroperitoneal,

2U transfusion

Voeltz MD, Attubato MJ, Feit F, et al. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-12-31A.

The REPLACE-2 Trial (N=6,010):

Mortality, Bleeding, Transfusion in Elderly PCI

0.4%

13.0%

0.5%

15.0%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

Major Bleeding Transfusions

= Yes

= No

p<0.0001 p=0.0001

30-D

ay M

ort

alit

y

Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613.

More: female, Caucasian, prior CVD, risk factors.Lower: BMI, Hgb, CrCl, tobacco.

Ischemic outcomes did not differ between elderly and younger patients.

Risk Score Predictive of Major Bleeding after PCI Using the Femoral Approach

Clinical + Procedural Variables

Risk factors

IABP

Age

Integer score

5

0 for 55 years; add 3 for every

10y over 55 Risk score Major

bleed* (%)

Female 3 0 1.0%

GPIIb/IIIa 3 Calculate 2 - 6 1.5%

7 - 9 2.6%

eGFR<60 2 10 5.4%

Anaemia 2

LMWH within 348h pre-PCI Nikolsky EHJ 2007;28:1936

CASE 1

Mrs K, a 72-year-old white woman sudden pressure in the middle of her chest

associated with shortness of breath, nausea, and

diaphoresis that started 2 hours previously.

blood pressure (BP) 98/64 mm Hg, Heart rate (HR) 105 bpm.

Past H/O Type 2 diabetes, hypertension, hyperlipidemia, stage 3 chronic kidney disease (glomerular filtration rate 50 mL/min/1.73 m2)

Social history 20 pack-year history of smoking

Which of the following puts this patient at greater risk for major hospital bleeding?

Hyperlipidemia Absence of S3 on physical examination Female sex History of angina

Identifying patients at increased risk of bleeding during acute coronary syndrome (ACS) helps reduce morbidity and mortality.

Subherwal et al formed the CRUSADE bleeding risk score from a database of 89,134 patients who presented with NSTEMI by identifying baseline risk factors for major hospital bleeding.

CRUSADE BLEEDING SCOREwww.crusadebleedingscore.org

Very low 20 or less Low 21-30 Moderate 31-40 High 41-50 Very high > 50

Based on Mrs K's symptoms and ECG, she is emergently taken for cardiac catheterization and possible PCI.

Bleeding avoidance strategies for this patient include which of the following?

Using a radial artery approach during catheterization.

Maintaining an activated clotting time (ACT) of 300 to 350 seconds when using eptifibatide during percutaneous coronary intervention.

Maintaining an ACT above 375 seconds with unfractionated heparin during percutaneous coronary intervention.

Using enoxaparin 1 mg/kg twice daily before catheterization.

STRATEGIES TO REDUCE BLEEDING RISK

There are several factors that should be considered to mitigate the bleeding risk in a patient undergoing catheterization:

1. access site (radial vs femoral),

2. antithrombotic and antiplatelet drugs

3. the choice and dosing of these agents.

Radial access is single most effective method to reduce bleeding.

In EASY trial, transradial PCI among 1348 patients, only 19 (1.4%) experience major bleeding.

In another randomized study by Kiemeneij et al of 900 patients undergoing balloon angioplasty,radial access was compared with both brachial artery and femoral artery access. The radial approach had the lowest incidence of vascular complications (0% radial, 2.3% brachial and 2.0% femoral) with no difference in procedural success.

In the RIVAL trial, which included 7021 patients with STEMI and NSTEMI, the primary outcome was not significantly different between the radial (3.7%) and femoral (4.0%) groups

There were significantly fewer pseudoaneurysms and large hematomas in the radial access group, but somewhat surprisingly, the rates of non-CABG major bleeding were similar to the transradial group.The authors speculated that this may have been due to an unusually low rate of bleeding in the femoral access group (0.9%) compared with previous studies such as the CURRENT-OASIS 7 trial(2.3%).

The RIFLE-STEACS trial included 1001 patients presenting with STEMI and showed a significantly lower rate of the primary end point and bleeding in the radial (13.6%) vs femoral (21.0%) access groups.

The transradial approach was also associated with a shorter hospital duration and a significant reduction in cardiac mortality (5.2% vs 9.2%; P =.020) and bleeding (7.8% vs 12.2%; P =.026).

Jolly et al. Am Heart J 2009;157:132-40

PROCEDURAL METHODS When using the femoral artery approach,

proper location of arterial puncture and sheath insertion can significantly reduce bleeding events, including retroperitoneal hematomas.

Arteriotomy in the common femoral artery above the bifurcation, but below the inferior epigastric artery, is associated with the lowest bleeding rate.

The use of fluoroscopy to identify the middle third of the femoral head can help to puncture into the femoral artery at the appropriate location.

The use of smaller sized sheaths (5 F) are associated with reduced bleeding.

FEMORAL ARTERY PUNCTURE LOCATION

COMPLICATIONS

LOW STICK: PUNCTURE BELOW THE FEMORAL BIFURCATION

PSEUDOANEURYSMHAEMATOMA ARTERIOVENOUS FISTULA

HIGH STICK: PUNCTURING THE INFERIOR EPIGASTRIC ARTERY

RETROPERITONEAL HAEMORRHAGE

POSTERIOR WALL PUNCTURE: PUNCTURE THROUGH THE BACK WALL OF THE ARTERY

RETROPERITONEAL HAEMORRHAGE

Bleeding avoidance strategies for this patient include which of the following?

Using a radial artery approach during catheterization.

Maintaining an activated clotting time (ACT) of 300 to 350 seconds when using eptifibatide during percutaneous coronary intervention.

Maintaining an ACT above 375 seconds with unfractionated heparin during percutaneous coronary intervention.

Using enoxaparin 1 mg/kg twice daily before catheterization.

STRATEGIES TO REDUCE BLEEDING RISK

PHARMACOLOGICAL STARTEGIES: Unfractionated heparin has traditionally been the

antithrombin of choice for PCI, with or without the addition of a GPI.

If a GPIIb/IIIa is used, the target activated clotting time (ACT) is between 200 and 250 s.

If no GPIIb/IIIa is used in conjunction with UFH, the desired ACT during the intervention is between 250 and 300 s.

ACT above 350 s has not only been demonstrated to increase the risk of bleeding, but also increase ischemic complications such as MI, death and revascularization

Since UFH are associated with platelet activation, the use of a GPI during PCI reduces periprocedural ischemic complications compared with UFH alone, especially in patients with ACS undergoing PCI however at the expense of increased bleeding, mostly at the vascular access site.

Indeed, the use of GPIs has been shown to be an independent risk factor for developing vascular access-site bleeding requiring a transfusion in several observational studies

( GRACE & NHLBI REGISTERY )

One strategy to reduce, the increased risk of bleeding with the addition of a GPI to heparin is to dose both agents appropriately.

The magnitude of misdosing of anticoagulants and antiplatelet agents has been underscored by (CRUSADE) registry.

Elderly patients and women with ACS were more likely to be overdosed.

Up to 25% of the increased risk of bleeding observed in females is attributable to overdosing of antithrombotic agents.

Therefore, it seems reasonable that appropriate dosing based on weight and renal clearance is an important step to reducing bleeding risk.

Excess Dosing of Antithrombotic therapy Underdosed

35

30

Recommended Mild Excess

Dose Group

Major Excess

25

20

15

10

5

0

25% of major bleeding may be attributable to excess dosing

UFH LMWH GP IIb/IIIa

Alexander JAMA 2004;294:3108-16.

UFH vs LMWH

The ESSENCE trial randomized 3171 patients with UA/NSTEMI to enoxaparin or UFH.

At 30 days, enoxaparin was associated with a significant reduction in ischemic events (19.8% vs 23.3%; P =.016) without an increase in major bleeding (6.5% vs 7.0%; P =.57).

Similarly the SYNERGY trial randomized 9978 patients with NSTEMI to receive enoxaparin or UFH in the presence of dual antiplatelet and GP IIa/IIIb inhibition.

In this setting, enoxaparin increased TIMI major bleeding (9.1% vs 7.6%; P =.008), but there was no difference in ischemic event rates between patients treated with either antithrombin during PCI.

The STEEPLE trial assigned patients to intravenous enoxaparin at 0.5 or 0.75 mg/kg, or weight-adjusted UFH to be given at the initiation of the procedure.

The primary outcome was non-CABG major bleeding occurring within 48 h. This was lowest in the enoxaparin 0.5 mg/kg arm. MI was also lowest in this arm; however, the mortality was higher, leading to early discontinuation of enrollment into the 0.5 mg/kg enoxaparin arm.

Although it appears that intravenous enoxaparin is associated with less bleeding compared with UFH, the inability to measure its effect at the bedside and the higher mortality rate in the low-dose enoxaparin arm of STEEPLE have limited its widespread acceptance for PCI.

Mrs K undergoes radial coronary angiography, which shows a 90% stenosis in her proximal LAD artery.The decision is made to perform PCI.

Which of the following options for anticoagulation during percutaneous coronary intervention (PCI) is associated with the lowest bleeding risk in this patient?

Heparin Heparin and eptifibatide Fondaparinux Bivalirudin

Since Mrs K is undergoing PCI, fondaparinux alone is not a good choice because it is associated with an increased incidence of catheter-related thrombosis.

In OASIS 5 trial,20,000 NSTEMI pts. were randomized to receive fondaparinux 2.5 mg daily or enoxaparin 1 mg/kg twice daily for a mean of 6 days.

Favored fondaparinux due to significant reduction in mortality seen at 30 days (2.9% vs 3.5%; P =.02). Major bleeding was significantly reduced with fondaparinux

However, there was a significantly increased rate of catheter-related thrombi in the fondaparinux group. Adding a small dose of heparin to fondaparinux eliminated this hazard without increasing bleeding complications.

DIRECT THROBIN INHIBTORS Bivalirudin, has been shown to reduce bleeding complications

compared with UFH or enoxaparin, with or without GPI. The first trial with bivalirudin in PCI was the Bivalirudin Angioplasty

Trial(BAT), which used a higher dose than that currently used in clinical practice.

The BAT trial randomly assigned 4312 patients with UA undergoing PCI to either bivalirudin or high-dose UFH.

Rate of both ischemic complications (7.9 vs 6.2%; p = 0.039) and major bleeding (9.3 vs 3.5%; p < 0.001) was lower in the bivalirudin group.

Modern dosing of bivalirudin was evaluated in the REPLACE-2 trial, which randomized patients undergoing elective or urgent PCI to :

1. UFH with planned GPIIb/IIIa or

2. Bivalirudin with provisional GPIIb/IIIa.

The bivalirudin strategy was statistically noninferior to the UFH plus GPI strategy.

There was no difference in ischemic end points between the two arms; there was, however, a 41% relative reduction in major bleeding events in the bivalirudin group (2.4 vs 4.1%; p <0.001).

In the ACUITY trial, patients were assigned to one of three anticoagulant strategies:

1. UFH or enoxaparin plus GPIIb/IIIa,

2. Bivalirudin plus GPIIb/IIIa, or

3. Bivalirudin alone.

Bivalirudin monotherapy was superior to either of the GPI arms with respect to the composite end point, a difference that was driven by a substantial reduction in major bleeding without any significant differences among the other individual end points at 30 days

Harmonizing Outcomes with Revascularization and Stents in AMI3602 pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…

Primary PCICABG – Medical Rx–

UFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)

Bivalirudin monotherapy(± provisional GP IIb/IIIa)

Aspirin, thienopyridine R 1:1

3006 pts eligible for stent randomization R 3:1

Bare metal EXPRESS stentPaclitaxel-eluting TAXUS stent

Clinical FU at 30 days, 6 months, 1 year, and thenyearly through 5 years; angio FU at 13 monthsClinical FU at 30 days, 6 months, 1 year, and thenyearly through 5 years; angio FU at 13 months

1.8

8.3

1.8

4.9

0

2

4

6

8

10

12

Reinfarction Major bleeding*

30 d

ay e

vent

rate

s (%

)Heparin + GPIIb/IIIa inhibitor (N=1802)Bivalirudin monotherapy (N=1800)

HORIZONS: 30 Day Adverse Events

*Not related to CABG** Plat cnt <100,000 cells/mm3

P<0.001

P = 0.90

Stone GW et al. NEJM 2008;358:2218-30

HORIZONS: 1-Year All-Cause Mortality

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

1800 1705 1684 1669 15201802 1678 1663 1646 1486

Mo

rtal

ity

(%)

0

1

2

3

4

5

Time in Months

0 1 2 3 4 5 6 7 8 9 10 11 12

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802) 4.8%

3.4%

HR [95%CI] =

0.69 [0.50, 0.97]

P=0.029

3.1%

2.1%

Δ = 1.0%

P=0.049

Δ = 1.4%

Mehran R et al. Lancet 2009:on-line

CASE CONTINUATION

Mrs K has a drug-eluting stent place in her LAD artery.In addition to 81 mg of aspirin daily, what other antiplatelet medication is associated with the lowest stent thrombosis risk in this patient?

Clopidogrel 75 mg daily for 1 year Ticagrelor 90 mg twice daily for 1 year Prasugrel 10 mg daily for 1 year None

The CLASSICS trial established clopidogrel as a safer alternative to ticlopidine.

In the PCI-CURE trial, 2658 patients who underwent PCI for NSTEMI were randomozed after 28 days post PCI to clopidogrel or placebo. There was a significant reduction in ischemic events among the group that received clopidogrel, with difference in major bleeding.

Clopidogrel has a relatively slow onset of action, and many patients -- notably those with diabetes -- are poor responders to clopidogrel.

Prasugrel was studied in the TRITON-TIMI 38 randomized trial of 13,608 patients with ACS scheduled for PCI to prasugrel (60-mg load,

10 mg daily) or clopidogrel (300-mg load, 75 mg daily).

The trial showed that prasugrel significantly reduced ischemic events compared to clopidogrel with a significant increase in non-CABG-related TIMI major bleeding.

 A post hoc analysis revealed that patients with a history of stroke or transient ischemic attack had a net harm from prasugrel.

Prasugrel is contraindicated in these patients because of an increased risk of intracranial hemorrhage. Additionally, there was no net benefit in patients 75 years or older or in those weighing less than 60 kg.

A lower maintenance dose of 5 mg daily is an option in such patients.

Interestingly, among the 3534 patients from the TRITON-TIMI 38 trial who underwent PCI for STEMI, prasugrel maintained improved efficacy at 30 days and 15 months without an excess in major bleeding compared to clopidogrel at 30 days. Similarly patients with diabetes appeared to derive particular benefit from prasugrel without an increased risk for bleeding. Net clinical benefit with prasugrel was greater for subjects with diabetes than for subjects without.Definite or probable stent thrombosis was halved in the prasugrel group compared with the clopidogrel-treated patients

The PLATO trial randomized 18,624 patients with ACS to receive either ticagrelor (180-mg load, 90 mg twice daily) or clopidogrel (300- to 600-mg load, 75 mg daily).

Ticagrelor was associated with a significant reduction in ischemic events, but non-CABG TIMI major bleeding was higher.

Ticagrelor was effective in patients with diabetes.

CASE CONTINUATION

Mrs K has a drug-eluting stent place in her LAD artery.In addition to 81 mg of aspirin daily, what other antiplatelet medication is associated with the lowest stent thrombosis risk in this patient?

Clopidogrel 75 mg daily for 1 year Ticagrelor 90 mg twice daily for 1 year Prasugrel 10 mg daily for 1 year None

Both prasugrel and ticagrelor reduce the risk of cardiovascular outcomes compared to clopidogrel in patients with STEMI.

The increased risk of Non-CABG TIMI major bleeding seen with both agents in a mixed ACS population was not seen among the subgroup of patients with STEMI and/or those undergoing PCI.

So far, there have been no large randomized trials directly comparing prasugrel and ticagrelor; Stent thrombosis rates were halved with prasugrel and cut by 27% with ticagrelor in their respective trials;

Additionally, prasugrel appeared to especially benefit patients like Mrs K who have type 2 diabetes. 

Had it been that medical management is appropriate startegy then what is the best long-term antiplatelet regimen for Mrs K in order to reduce her risk of death, recurrent myocardial infarction, or stroke?

Aspirin 81 mg and clopidogrel for 1 year Aspirin 81 mg and prasugrel 10 mg for 1 year Aspirin 81 mg and ticagrelor 90 mg twice daily for 1 year Aspirin 325 mg and ticagrelor 90 mg twice daily for 6 months

Prasugrel is not indicated for patients who are medically managed. In the TRILOGY-ACS trial comparing prasugrel and clopidogrel in 7243 patients with ACS who were medically managed, there was no significant difference in the composite ischemic end points at a median follow-up of 17 months.

Which of the following should we monitor closely because it carries the greatest increased risk for mortality among patients undergoing PCI?

Formation of a pseudoaneurysm Access site bleeding Non-access site bleeding Radial artery bruit

Complications that can occur during: pseudoaneurysm formation, arteriovenous fistula formation, development of a hematoma at the access site, retroperitoneal hemorrhage, intracranial bleeding, or gastrointestinal bleeding.

Non-access site bleeding is associated with the greatest mortality.

Relative Risk of 1-year Mortality Associated with Bleeding and Source (unadjusted)

2.3

5.75.5

5.25.4

0.0

1.0

2.0

3.0

4.0

5.0

6.0

Access Only Both Non-AccessOnly

No Location All Non-Access

Re

lativ

e R

isk

1-Y

ea

r M

ort

alit

y

P<0.0001 for all bleeding versus none

Verheugt JACC Cardio Interv 2011;4:191-7:

Impact of Bleeding on Outcome

…has long been underestimated

A number of studies have now demonstrated the association between bleeding complications after PCI and adverse outcomes.

Specifically, adverse cardiac ischemic events and death correlate in a stepwise fashion with the severity of the bleeding complications in both the short and intermediate term.

Major Bleeding is Associated with a Subsequent Increase in Late Mortality

Pooled Analysis of OASIS Registry, OASIS2, CURE

12.8% Bleeding

No Bleeding 2.5%

0 5 10 15 20 25 30Days

Eikelboom JW et al. Circulation 2006;114: 774 - 782

In the REPLACE-2 trial, which compared UFH with planned GPIIb/IIIa to bivalirudin plus provisional GPIIb/IIIa, 3.2% of the 6010 patients experienced major bleeding.

Mortality rates at 30 days, 6 months and 1 year were all significantly higher in those with major hemorrhage compared with those without.

Major bleeding was found to be an independent predictor of 1-year mortality with an OR of 2.66 (95% CI: 1.44–4.92; p = 0.002).

ACUITY (N=13,819)Impact of MI and Major Bleeding in the First

30 Days on Risk of Death Over 1 Year

Mo

rta

lity

(%)

Days from Randomization

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

25

10

20

Estimate

Patients with MI (N=705) 11.4%

1 year

Patients with Major Bleed (N=645) 14.9%

Patients w/o Major Bleed (N=13,168) 3.6%

Patients w/o MI (N=13,108) 3.8%

3.8%3.6%

14.9%

11.4%

Patients with major bleeding also experienced higher rates of myocardial infarction (MI), unplanned revascularization, stent thrombosis, thrombocytopenia and longer lengths of hospital stay

If bleeding kills…..

Can blood transfusion save lives?

Transfusion > Mortality

24000 pts with ACS analyzed from GUSTO IIb, PURSUIT and PRAGON.

10% underwent transfusion.

Transfusion was associated with HR of 3.94 [CI 3.26-4.75] for death.

Predicted probability of 30 day death was higher with transfusion at nadir HCT > 25%.

Rao et al. JAMA. 2004;292:1555-1562

There was also a link between the number of units transfused and 1-year mortality with the OR of 1-year death being 1.47 per unit transfused.

The reasons why blood transfusions correlate to a higher risk of adverse outcomes are unclear.

Proposed mechanisms include include shifts in the oxyhemoglobin dissociation curve, increases in systemic inflammation, and the lack of nitric oxide in packed red cells, all of which lead to paradoxical decreases in tissue oxygenation as transfusion is used to increase hemoglobin.

Transfusion > Mortality

Doyle et al J Am Coll Cardiol 2009;53:2019–27

Older blood > higher mortality

Red cell transfusion in post-CABG and valve pts was studied.

3000 pts were given old blood (> 2 weeks) and 3000 pts were given new blood (< 2 weeks).

At 1 year, mortality was significantly less in pts given new blood (7.4% vs 11%, p < 0.001).

Koch et al. N Engl J Med 2008;358:1229-39.

CASE 2

Mr H is a 61-year-old man presents with heartburn that started about 4 hours previously. After taking an antacid without improvement, he decided to seek help. Upon further questioning, Mr H reported experiencing fatigue while working in his garden lately. His vital signs were BP 140/84 mm Hg, HR 96 bpm, RR 15 breath/min, and oxygen saturation 96% on room air. This physical exam was unremarkable. An initial electrocardiogram showed normal sinus rhythm with no ST-segment changes.

Past H/O DM, Stage 4 CKD present

Mr H is given 325 mg of aspirin. The decision is made to anticoagulate him while his cardiac enzymes are cycled.

Based on Mr H's bleeding risk, what is the most appropriate initial anticoagulation therapy for this patient?

Unfractionated heparin maintaining an activated partial thromboplastin time (aPTT) of 50 to 70 seconds

Fondaparinux 5.0 mg/d Enoxaparin dosed at 1 mg/kg every 12 hours Bivalirudin 1.75 mg/kg/h continuous infusion

It is not yet established that Mr H has an ACS or whether he will be managed conservatively or invasively. Unfractionated heparin is appropriate for either management strategy;as Mr H has stage 4 CKD, it is important to titrate the dose by monitoring his aPTT. Although enoxaparin may be a reasonable choice for this patient, the dose presented is not adjusted for Mr H's renal dysfunction.

Fondaparinux is contraindicated when the GFR <30 mL/min/1.73 m2.

Bivalirudin has a favorable bleeding risk in chronic kidney disease but has not been studied adequately in patients managed conservatively.

Six hours later,cardiac enzymes were positive. Mr H is loaded with 180 mg of ticagrelor. The decision is made to pursue invasive risk stratification.

If left heart catheterization shows coronary anatomy appropriate for coronary artery bypass surgery, in how many days after ticagrelor discontinuation can Mr H proceed to CABG in order to minimize bleeding risk?

1-2 days 2-3 days 3-4 days 5-7 days

The benefits of early initiation (prior to cardiac catheterization) of P2Y12 receptor antagonists in patients with NSTEMI have to be balanced against the increased risk for CABG bleeding should emergent surgery be required.

If CABG is indicated and the patient is stable, it is ideal to delay surgery until levels of platelet aggregation have normalized.

Current ACCF/AHA guidelines for the management of patients with NSTEMI recommend withholding clopidogrel and ticagrelor for at least 5 days and prasugrel for 7 days before undergoing CABG if possible.

The following night, Mr H develops sudden abdominal pain and vomits a small amount of blood and then has melena; upper endoscopy reveals gastritis with no active bleeding and no ulcer.

Of the following choices, what is the best medication to help prevent gastric bleeding in Mr H while he continues his dual antiplatelet therapy regimen?

Ranitidine 150 mg twice daily Omeprazole 20 mg daily Famotidine 40 mg daily Cimetidine 800 mg every night at bedtime

 In patients who are at high risk for GI bleeding, it is recommended that a proton pump inhibitor (PPI) be administered.

The ASTRONAUT study showed that the PPI omeprazole was more effective than the histamine receptor-2 blocker (H2 blocker) ranitidine for healing gastroduodenal ulcers or erosions in patients who continued NSAID use.

However, there is controversy regarding the potential interaction of certain PPIs with thienopyridines, notably the interaction of omeprazole and clopidogrel because of a common metabolism via the cytochrome P450 pathway. Although most of the data are observational, the one randomized trial that investigated the issue did not show an interaction.

The COGENT trial was designed to examine a combination clopidogrel-omeprazole preparation vs clopidogrel alone. The results showed a significant reduction in gastrointestinal events in the omeprazole arm without a significant increase in cardiovascular events

 Some studies suggest that the interaction with clopidogrel may not occur with pantoprazole.

The TRITON-TIMI 38 study did not show higher event rates in patients assigned prasugrel who were taking PPIs compared with those not taking PPIs.

Ticagrelor is a direct-acting P2Y12 inhibitor that does not require biotransformation and is thus not affected by PPI coadministration. 

How to manage POST PCI BLEED

Prevention of Bleeding : Recommendations

� Assessment of bleeding risk is an important component of the decision making process (I-A).

� The anti-thrombotic treatment should be selected according to bleeding risks. (I-C)

� Dosing regimens of anti-thrombotic therapy should be adjusted based on weight & renal function. (I-C)

� Crossover between UFH & LMWH should be avoided.

� Anticoagulation should be discontinued after PCI (unless specific indication exists).

� Selective downstream use of GPI should be preferred to unselective upstream use.

� Radial access should be preferred in pts at high risk of bleeding

Wijns W et al. Eur Heart J 2010;31:2501-55. Bassand JP et al. Eur Heart J 2007;28:1598-1660. Steg PG et al. Eur Heart J 2011.

Management of Bleeding : Recommendations

� Minor bleeding :

- no interruption of active treatments

(I-C)

� Major bleeding : - interruption and/or neutralization of both anticoagulant and antiplatelet therapy, unless bleeding can be adequately controlled by specific haemostatic interventions (I-C)

� Blood transfusions :

- may have deleterious effects on outcome and should therefore be

considered individually, but witheld in haemodynamically stable patients without overt bleeding with haematocrit >25% or haemoglobin level >8g/dL (I-C)

Wijns W et al. Eur Heart J 2010;31:2501-55. Bassand JP et al. Eur Heart J 2007;28:1598-1660. Steg PG et al. Eur Heart J 2011.

Bleeding occurred in 7328 [2.4%] of patients

38

12.818.7

5.4

25 Entry Site

Retroperitoneal

GIT

Genitourinary

Other

Circ Cardiovasc Intervent. 2009;2:222-229

ACCESS SITE BLEEDING

Haematoma Free bleeding

Haematoma is as significant complication when it has a diameter of more than 6 cm.

Incidence 1-5%

Usually resolves over 1-2 weeks.

HEMOSTATIC METHODS

MANUAL COMPRESSION ASSIST DEVICES MECHANICAL COMPRESSION SUTURE BASED CLOSURE DEVICES PLUG BASED SEALING DEVICES ELECTRICITY BASED SEALING PADS

MANUAL COMPRESSION

MANUAL COMPRESSION ASSIST DEVICES

COMPASS SYSTEM VASCULAR C-CLAMP

MECHANICAL COMPRESSION

FEMO STOP SYSTEM SAFEGUARD

PERCLOSE(suture based closure device)

ANGIOSEAL(plug based sealing device)

STARCLOSE DEVICE

Preventing Access Site bleeding Puncture Closing Devices vs Manual Compression

Koreny M et al. JAMA 2004;291:350-57.

G.I BLEEDING

At least half of GI bleeds after PCI occur during the index admission or within 30 days with an expected incidence of approximately 1%

Among the upper GI bleed post PCI, most common sites of bleeding are: gastric erosions (20.2%), followed by duodenal ulcers (14.3%), esophagitis (13.1%), Mallory–Weiss tears (13.1%), duodenitis (7.1%) and esophageal erosions (7.1%).

It appears, from this series at least, that variceal bleeds are uncommon (1.2%).

Management of GI Bleed Post PCI

BLOOD TRANSFUSION: when bleeding has been accompanied by hemodynamic compromise, a significant fall in hemoglobin (>3 g/dl) or by the finding of high-risk endoscopic stigmata for rebleeding

PPI: Omeprazole infusion has been shown to reduce rebleeding rate. Once the ulcer is healed and helicobacter pylori eradicated, treatment with aspirin and a PPI has a lower risk of GI bleeding than clopidogrel monotherapy without a PPI.

Patients should undergo diagnostic and therapeutic gastroscopy within 24 h, after adequate resuscitation and hemodynamic stabilization.

Standard therapeutic endoscopic techniques to control bleeding are safe to use in patients post-PCI. Theoretically, intramural adrenaline may be absorbed systemically and potentially reach the myocardium, producing unwanted sympathetic stimulation. A small study of patients demonstrated that adrenaline does reach the systemic circulation; however, there were no cardiac complications.

Anticoagulants & Antiplatelets

Decision will be based upon the competing risks of ongoing hemorrhage versus that of further ischemic coronary events, in particular in-stent thrombosis.

Wherever possible, antiplatelet therapy must be continued.

Continued antiplatelet therapy and concurrent anti-ulcer treatment would seem logical in the context of recent stent implantation and upper GI bleeding.

The risk of recurrent bleeding and death can be predicted from the patients condition on admission combined with endoscopic findings—the Rockall Score

A score of less than 3 carries an excellent prognosis, whilst a score of greater than 8 predicts a high risk of death.

ROCKALL SCORE

RETROPERITONEAL HAEMM

Relatively rare (0.5%) but fatal complication ( mortality rate 6.6%)

Risk factors:1. High femoral artery puncture above the inguinal ligament

2. Female gender

3. BSA <1.8 m2

4. Emergency procedure

5. H/O COPD

6. Cardiogenic shock

7. Use of preprocedural heparin or GPIIb/IIIa inhibitors

8. Sheath size ≥ 8 F

9. Use of Vascular closure devices (VCD)

SUSPECT WHENEVER PATIENT DEVELOPS:

1. Unexplained hypotension

2. Fall in haematocrit

3. Ipsilateral flank pain following procedure

Diagnosis by USG or CT

Conclusions:

A strong association exists between bleeding and higher mortality in patients with acute coronary syndromes.

Key to improved patient outcomes: Identify patients at high risk of bleeding. Institute strategies to lower bleeding while still

yielding a net clinical benefit for patients.

Inhibition of platelet aggregation

High risk ofischemic events

High risk ofbleeding events

Ris

k o

f an

y e

ve

nt

Ris

k o

f an

y e

ve

nt

“Sweet spot”

Ischemic risk Bleeding risk

Balancing Safety and Efficacy

Ferreiro & Angiolillo. Thromb Haemost 2010 (in press)

ConclusionsAs most drugs which ↓ ischemia also ↑ bleeding, the

offsetting impact of adverse ischemic and hemorrhagic events must be carefully examined

The net balance of ischemia and bleeding may vary tremendously with the risk profile of the individual pt for each complication, and the follow-up duration

Models are needed to assess a patient’s risk for bleeding as well as ischemic complications to further enhance treatment of the patients with therapies that are efficacious and also safe.